Circadian alterations during early stages of Alzheimer's disease are associated with aberrant cycles of DNA methylation in BMAL1

Alzheimers Dement. 2017 Jun;13(6):689-700. doi: 10.1016/j.jalz.2016.10.003. Epub 2016 Nov 22.


Introduction: Circadian alterations are prevalent in Alzheimer's disease (AD) and may contribute to cognitive impairment, behavioral symptoms, and neurodegeneration. Epigenetic mechanisms regulate the circadian clock, and changes in DNA methylation have been reported in AD brains, but the pathways that mediate circadian deregulation in AD are incompletely understood. We hypothesized that aberrant DNA methylation may affect circadian rhythms in AD.

Methods: We investigated DNA methylation, transcription, and expression of BMAL1, a positive regulator of the circadian clock, in cultured fibroblasts and brain samples from two independent cohorts of aging and AD.

Results: DNA methylation modulated rhythmic expression of clock genes in cultured fibroblasts. Moreover, rhythmic methylation of BMAL1 was altered in AD brains and fibroblasts and correlated with transcription cycles.

Discussion: Our results indicate that cycles of DNA methylation contribute to the regulation of BMAL1 rhythms in the brain. Hence, aberrant epigenetic patterns may be linked to circadian alterations in AD.

Keywords: Alzheimer's disease; BMAL1; Brain; Circadian clock; Circadian rhythms; DNA methylation; Epigenetics; Fibroblasts; Methylation cycles; Neurodegeneration.

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism*
  • Aged, 80 and over
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Case-Control Studies
  • Cells, Cultured
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology*
  • DNA Methylation*
  • Female
  • Fibroblasts / metabolism
  • Frontal Lobe / metabolism
  • Gene Expression
  • Humans
  • Male
  • Transcription, Genetic


  • ARNTL Transcription Factors
  • BMAL1 protein, human